Results from a first-in-human phase 1B study of a complement factor H inhibitor (GT103) in patients with non-small cell lung cancer (NSCLC).
Authors: Jeffrey Melson Clarke, Tom Stinchcombe, Lin Gu, Hirva Mamdani, Scott Joseph Antonia, George R. Simon, Guru P. Sonpavde, Neal E. Ready, Jeffrey Crawford, Michael Campa, Elizabeth Gottlin, Ryan Bushey, James Emmett Herndon, Edward Patz
Journal: Journal of Clinical Oncology (2023)

9128 Background: GT103 is a first-in-class IgG3 monoclonal antibody that was derived from a single human B cell and inhibits complement factor H (CFH). CFH is implicated in cancer immune evasion and overexpression portends a poor prognosis in multiple malignancies. CFH regulates C3 convertase in the alternative pathway of the complement cascade, limiting downstream opsonization and membrane attack complex formation. Monoclonal antibody inhibition of CFH facilitates complement-dependent tumor cell lysis, modulates the adaptive immune response, and inhibits tumor growth. Methods: GT103 is being evaluated in a multi-institutional, first-in-human, phase Ib study in patients with advanced stage, refractory NSCLC. A standard ‘3+3’ dose escalation schema was used across four dose levels, with treatment given until disease progression or unacceptable toxicity. Dose limiting toxicity (DLT) observation period included cycle 1 and radiographic disease assessment was performed every 6 weeks. We have previously reported that no DLT was seen at the highest two dose levels of 3 mg /kg or 10 mg/kg administered IV every 3 weeks. Two expansion cohorts have now been opened at 10 mg/kg IV every 2 week and 15 mg/kg every 3 weeks dose levels allowing up to 6 patients at each dose level. We herein present updated clinical outcomes and analysis of correlative biomarkers. Results: As of February 3, 2023, twenty-five patients have been treated, with a median follow up of 230 days. Five of the 21 patients in the dose escalation cohort demonstrated stable disease by RECIST criteria. In the 10 mg/kg dose level, one patient has experienced prolonged disease stabilization and has received 12 cycles to date with tumor reduction on CT. The DLT period is ongoing for two patients enrolled in the 10 mg/kg IV every 2 weeks and two patients in the 15 mg/kg every 3 weeks expansion cohorts. Soluble C5b-9 (s C5b-9) is a candidate pharmacodynamic biomarker for GT103 and was measured at baseline and at day 15 from patients in all four dose escalation levels (0.3, 1, 3, 10 mg/kg). An increase in sC5b-9 was found in 13 of 21 patients at day 15. A marked doubling of the baseline sC5b-9 level was demonstrated in a subset of patients by day 15 indicative of biologic activity. Conclusions: GT103 is well tolerated in heavily pretreated advanced NSCLC population. Early clinical activity has been demonstrated to date with stable disease seen in 24% of patients. Updated clinical results and correlative data will be presented. A separate phase 2 study of combination GT103 with pembrolizumab is planned for patients with refractory NSCLC. Trial Registration: The study was approved by Duke University IRB with approval number Pro00104564. Clinical trial information: NCT04314089 .